genetic factors and the directionality of comorbid disorders university of pittsburgh michael...
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Genetic Factors and the Genetic Factors and the Directionality of Comorbid Directionality of Comorbid
DisordersDisorders
Genetic Factors and the Genetic Factors and the Directionality of Comorbid Directionality of Comorbid
DisordersDisorders
University of Pittsburgh
Michael VanyukovMichael Vanyukov
Supported by NIDA grants Supported by NIDA grants R01DA011922, P50DA005605, R01DA019157, R01DA011922, P50DA005605, R01DA019157,
K02DA018701 K02DA018701
[email protected]@pitt.edu
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Getting to the root(s)Getting to the root(s)“The active ingredient in Roundup moves through the weed to kill the root.”
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Phenotyping SUDPhenotyping SUDPhenotyping SUDPhenotyping SUD
Dx of substance dependence:3 out of nine symptoms 466 combinations
Arbitrary phenotypes—ICD-m, DSM-n
Staging—opportunistic
Mixed effects: stimulants & depressants
And a little bit of this'd get you up
And a little bit of that'd get you down Mark Knopfler “Junkie Doll”
)!(!
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Liability, the conceptLiability, the conceptLiability, the conceptLiability, the concept
““......to express not only the individual to express not only the individual innate tendencyinnate tendency to develop or to develop or contract the disease, i.e., his contract the disease, i.e., his susceptibility in the usual sense, but susceptibility in the usual sense, but also the whole combination of also the whole combination of external circumstancesexternal circumstances that make him that make him more or less likely to develop the more or less likely to develop the diseasedisease...” ...”
Falconer (1965) Falconer (1965)
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Liability distributionLiability distributionLiability distributionLiability distribution
LiabilityLiability
AffectedAffected
thresholdthreshold phenotypephenotype
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Shared liability varianceShared liability variance
Tsuang et al., Tsuang et al., Harvard Rev PsychiatryHarvard Rev Psychiatry, 9: 267-279, 2001, 9: 267-279, 2001
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More sharingMore sharing
Kendler et al., Am J Psychiatry 160: 687–695, 2003Kendler et al., Am J Psychiatry 160: 687–695, 2003
0.74 0.62 0.62 0.52 0.58 0.23
CannabisCannabisCocaineCocaine HallucHalluc SedatSedat StimulStimul OpiateOpiate
AAcc
SScc/U/Ucc
0.01/0.09 0.00/0.14 0.05/0.25 0.07/0.34 0.06/0.16 0.00/0.64
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Kendler, K. S. et al. Arch Gen Psychiatry 2003;60:929-937.
Psychiatric and drug abuse disordersPsychiatric and drug abuse disorders
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Common sources of Common sources of variationvariation
PrePre-use-use TemperamentTemperament PersonalityPersonality CognitionCognition BehaviorBehavior Self-medicationSelf-medication
PostPost-use-use Positive Positive
reinforcementreinforcement Negative Negative
reinforcementreinforcement
Biobehavioral self-regulation
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PrefrontalPrefrontalcortexcortex
NucleusNucleusaccumbensaccumbens
Substantia nigra
HippocampusHippocampus Locus Locus coeruleuscoeruleus
CerebellumCerebellum
Ventral Ventral tegmental tegmental
areaarea
ColliculusColliculus
PeriaqueductalPeriaqueductal graygray areaarea
ALCOHOLALCOHOL
OPIATESOPIATES
COCAINE & COCAINE & AMPHETAMINESAMPHETAMINES
StriatumStriatum
Dopamine Dopamine pathwaypathway
AmygdalaAmygdala
The drug-activated mesocorticolimbic dopamine The drug-activated mesocorticolimbic dopamine pathwaypathway
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Sources of SUD risk Sources of SUD risk variationvariation
Sources of SUD risk Sources of SUD risk variationvariation
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Comorbidity models Comorbidity models
Chance, bias, stratificationChance, bias, stratification Alternate forms (single liability)Alternate forms (single liability) Multiformity (having one increases Multiformity (having one increases
probability of another, threshold-probability of another, threshold-dependent)dependent)
Three independentThree independent Correlated liabilities (threshold-Correlated liabilities (threshold-
independent)independent)– correlatedcorrelated– one causes anotherone causes another– reciprocal causationreciprocal causation
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Subsample of modelsSubsample of models
Rhee et al. J Abnorm Psychol, 114:346-362, 2005
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Genetics in SUD riskGenetics in SUD riskGenetics in SUD riskGenetics in SUD risk
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It’s a long way …It’s a long way …It’s a long way …It’s a long way …
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Dynamic liability: Tracking etiology Dynamic liability: Tracking etiology and comorbidity of SUDand comorbidity of SUD
Dynamic liability: Tracking etiology Dynamic liability: Tracking etiology and comorbidity of SUDand comorbidity of SUD
Risk
Drug use
SUD
Time 0 Initial liability
SUDthreshold
Liability
Ag
e
R
Time 2
Time 1
R
R
Epigenetictrajectory
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Genetics & Genetics & comorbiditycomorbidity Behavior geneticsBehavior genetics
– genetic and environmental genetic and environmental correlationscorrelations
– developmental trackingdevelopmental tracking Molecular geneticsMolecular genetics
– association/linkageassociation/linkage– mediation by intermediate traitsmediation by intermediate traits
““Hybrids”Hybrids”
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Family historyFamily history
Faster physiological maturationFaster physiological maturation Detachment from parentsDetachment from parents Homophilic peer Homophilic peer
selection/contagionselection/contagion Dysregulation/disinhibitionDysregulation/disinhibition MaladjustmentMaladjustment SU/SUDSU/SUD
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LF
123
Transmissible causal variables (e.g., genetic polymorphisms, neurochemical processes, transmissible environment)
4
LP
nontransmissible environment
Psy
chol
ogic
al
varia
bles
LP – parental liabilityLF – son’s liability
Determination of SUD liabilityDetermination of SUD liabilityDetermination of SUD liabilityDetermination of SUD liability
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Diagnosis HR 95% CI P ADHD 2.81 1.42-5.55 0.003 CD 7.17 2.78-18.52 0.00005ODD 2.20 1.04-4.63 0.038
DBD and the rate of DBD and the rate of SUDSUD
dysregulation
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DRD4-ERP-DRD4-ERP-DisinhibitionDisinhibition Family-based analysis (FBAT)Family-based analysis (FBAT) Promoter region (-521) SNPPromoter region (-521) SNP ERP—ND: p=.02ERP—ND: p=.02 SNP—>P300: p=.004SNP—>P300: p=.004 SNP—>ND: p=.003SNP—>ND: p=.003 SNP—>ND|P300: p=.85SNP—>ND|P300: p=.85
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Parenting & MAOAParenting & MAOA
Dependent Sample Predictor Hazard ratio (95% CI) P CD full dad 0.504 (0.289-0.879) .016 momdad 0.652 (0.456-0.932) .019 4R dad 0.380 (0.179-0.805) .011 mom 1.601 (0.989-2.591) .055 3R dad 0.796 (0.343-1.850) .597 mom 1.099 (0.534-2.265) .797 ADHD full momdad 1.558 (1.031-2.353) .035 dadMAO 3.299 (1.479-7.356) .004 4R dad 1.974 (1.230-3.168) .005 momdad 1.799 (1.057-3.062) .030 3R dad 0.574 (0.256-1.284) .177 momdad 1.604 (0.719-3.578) .249 SUD full MAO 0.382 (0.155-0.940) .036
Vanyukov et al. (in press) Psychiatric Genetics
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MAOA & SUDMAOA & SUD
Low activityLow activity increase in the riskincrease in the risk limbic volume reductions, limbic volume reductions,
hyperresponsive amygdala during hyperresponsive amygdala during emotional arousal, diminished emotional arousal, diminished reactivity of regulatory prefrontal reactivity of regulatory prefrontal regions (Meyer-Lindenberg et al., regions (Meyer-Lindenberg et al., 2006) 2006)
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Drug use severityDrug use severityDrug use severityDrug use severityDrug Use Screening Inventory substance use problems scale
94 male Caucasian adolescents (12-18 years of age) with a DSM-IV diagnosis of Substance Dependence related to illicit drugs
Polymorphisms in DRD1-DRD5 genes
Two-way ANOVA, testing main effects and interactions between D1- and D2-family genes
Trait
Sample
Genes
Analysis
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Interactions as Interactions as expected expected
Interactions as Interactions as expected expected
PredictorPredictor setssets ddff FF pp DRD1.1DRD1.1 22 2.282.28 ..108108 DRD2DRD2 11 0.020.02 .898.898 DRD1.1DRD1.1DRD2DRD2 11 4.394.39 .039.039 DRD1.1DRD1.1 22 3.633.63 .031.031 DRD3DRD3 44 1.091.09 .369.369 DRD1.1DRD1.1DRD3DRD3 66 2.292.29 .044.044 DRD1.7DRD1.7 22 4.474.47 .015.015 DRD3DRD3 44 0.720.72 .584.584 DRD1.7DRD1.7DRD3DRD3 66 2.602.60 .025.025
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Candidate system Candidate system genesgenesComorbidity helps:multiple hits•cross-verify•identify pathways•support the
gene’s role
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c3c3
GGcc
h3h3
e3e3
EEc1c1
GGpp
hh
ee
EEpp
pp
EEc3c3 EEc2c2
c2c2
h2h2
e2e2
c1c1
h1h1
e1e1
T1 T2 T3
Dynamic Dynamic Dynamic Dynamic
frozen
birth
time
Note: G×E omitted
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Genetic rootsGenetic rootsGenetic rootsGenetic roots
… environmental “Roundup”?